chr10-33263767-C-T

Variant names:

• chr10-33263767-C-T
• rs2070296
• NM_003873.7:c.537G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_003873.7(NRP1):​c.537G>A​(p.Val179Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.181 in 1,612,932 control chromosomes in the GnomAD database, including 28,913 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Synonymous variant affecting the same amino acid position (i.e. V179V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.21 (3776 hom., cov: 32)
  • Exomes 𝑓: 0.18 (25137 hom.)
• Consequence: NRP1 NM_003873.7 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.0240
• Publications: 29 publications found

Genes affected

NRP1 (HGNC:8004): (neuropilin 1) This gene encodes one of two neuropilins, which contain specific protein domains which allow them to participate in several different types of signaling pathways that control cell migration. Neuropilins contain a large N-terminal extracellular domain, made up of complement-binding, coagulation factor V/VIII, and meprin domains. These proteins also contains a short membrane-spanning domain and a small cytoplasmic domain. Neuropilins bind many ligands and various types of co-receptors; they affect cell survival, migration, and attraction. Some of the ligands and co-receptors bound by neuropilins are vascular endothelial growth factor (VEGF) and semaphorin family members. This protein has also been determined to act as a co-receptor for SARS-CoV-2 (which causes COVID-19) to infect host cells. [provided by RefSeq, Nov 2020]

NRP1 Gene-Disease associations (from GenCC):

• congenital heart disease

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 10-33263767-C-T is Benign according to our data. Variant chr10-33263767-C-T is described in ClinVar as Benign. ClinVar VariationId is 3059652.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-0.024 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.455 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003873.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRP1	NM_003873.7	MANE Select	c.537G>A	p.Val179Val	synonymous	Exon 4 of 17	NP_003864.5
	NRP1	NM_001244972.2		c.537G>A	p.Val179Val	synonymous	Exon 4 of 17	NP_001231901.2
	NRP1	NM_001244973.2		c.537G>A	p.Val179Val	synonymous	Exon 4 of 17	NP_001231902.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRP1	ENST00000374867.7	TSL:1 MANE Select	c.537G>A	p.Val179Val	synonymous	Exon 4 of 17	ENSP00000364001.2	O14786-1
	NRP1	ENST00000395995.5	TSL:1	c.537G>A	p.Val179Val	synonymous	Exon 4 of 16	ENSP00000379317.1	E9PEP6
	NRP1	ENST00000374823.9	TSL:1	c.537G>A	p.Val179Val	synonymous	Exon 4 of 11	ENSP00000363956.5	Q5T7F0

Frequencies

GnomAD3 genomes AF: 0.212 AC: 32222 AN: 151816 Hom.: 3776 Cov.: 32

Gnomad AFR AF: 0.291

Gnomad AMI AF: 0.355

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.165

Gnomad EAS AF: 0.472

Gnomad SAS AF: 0.200

Gnomad FIN AF: 0.175

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.161

Gnomad OTH AF: 0.200

GnomAD2 exomes AF: 0.201 AC: 50578 AN: 251416 AF XY: 0.197

Gnomad AFR exome AF: 0.298

Gnomad AMR exome AF: 0.181

Gnomad ASJ exome AF: 0.166

Gnomad EAS exome AF: 0.472

Gnomad FIN exome AF: 0.166

Gnomad NFE exome AF: 0.164

Gnomad OTH exome AF: 0.183

GnomAD4 exome AF: 0.177 AC: 259191 AN: 1460996 Hom.: 25137 Cov.: 32 AF XY: 0.177 AC XY: 128723 AN XY: 726892

African (AFR) AF: 0.299 AC: 10004 AN: 33464

American (AMR) AF: 0.180 AC: 8070 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.164 AC: 4298 AN: 26128

East Asian (EAS) AF: 0.442 AC: 17531 AN: 39692

South Asian (SAS) AF: 0.187 AC: 16097 AN: 86234

European-Finnish (FIN) AF: 0.162 AC: 8639 AN: 53416

Middle Eastern (MID) AF: 0.126 AC: 729 AN: 5768

European-Non Finnish (NFE) AF: 0.164 AC: 182309 AN: 1111206

Other (OTH) AF: 0.191 AC: 11514 AN: 60364

GnomAD4 genome AF: 0.212 AC: 32259 AN: 151936 Hom.: 3776 Cov.: 32 AF XY: 0.214 AC XY: 15858 AN XY: 74234

African (AFR) AF: 0.291 AC: 12064 AN: 41438

American (AMR) AF: 0.176 AC: 2694 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.165 AC: 572 AN: 3468

East Asian (EAS) AF: 0.470 AC: 2413 AN: 5132

South Asian (SAS) AF: 0.200 AC: 962 AN: 4800

European-Finnish (FIN) AF: 0.175 AC: 1840 AN: 10538

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.161 AC: 10935 AN: 67980

Other (OTH) AF: 0.201 AC: 423 AN: 2108

Alfa AF: 0.175 Hom.: 4522

Bravo AF: 0.218

Asia WGS AF: 0.332 AC: 1153 AN: 3478

EpiCase AF: 0.164

EpiControl AF: 0.158

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	NRP1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	0.78
DANN	Benign	0.61
PhyloP100		-0.024
PromoterAI		0.0023	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=297/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2070296; hg19: chr10-33552695; COSMIC: COSV55162348; COSMIC: COSV55162348;